2. Academic Validation
  3. Synthesis and biological evaluation of 4-substituted fluoronucleoside analogs for the treatment of hepatitis B virus infection

Synthesis and biological evaluation of 4-substituted fluoronucleoside analogs for the treatment of hepatitis B virus infection

  • J Med Chem. 2015 May 14;58(9):3693-703. doi: 10.1021/jm5012963.
Qinghua Yang 1 2,  Jinfeng Kang 1,  Liyun Zheng 3,  Xue-Jun Wang 4,  Na Wan 3,  Jie Wu 1,  Yan Qiao 1,  Pengfei Niu 1,  Sheng-Qi Wang 4,  Youmei Peng 1 3,  Qingduan Wang 3,  Wenquan Yu 1,  Junbiao Chang 1 2
Affiliations

Affiliations

  • 1 †College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, PR China.
  • 2 ⊥Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, PR China.
  • 3 ‡Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, PR China.
  • 4 §Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
PMID: 25905540 DOI: 10.1021/jm5012963
Abstract

A series of 4-substituted fluoronucleosides have been synthesized in order to address the toxicity issue of the parent compound 7, and after in vitro evaluation, the cyclopropylamino analog 1f was selected for in vivo study. In mice, this compound exhibited a significantly improved toxicity profile. Administered orally, compound 1f was well-tolerated at a dose up to 3 g/kg and showed insignificant toxicity on white blood cells and a low mutagenic effect at dosages up to 80 mg/kg (single) or 20 mg/kg/day (5 days). In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (74.2 and 82.1%, respectively) were markedly reduced by the treatment of 1f at a dose of 1 mg/kg/day for 10 days. In addition, both the viral DNA levels had a lower degree of recovery after withdrawal of the test compound for 3 days.

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